PROJECT SUMMARY/ABSTRACT Although it has been known for over three decades that thyrotropin (thyroid stimulating hormone [TSH]) is produced by cells of the immune system, the physiologic significance of that remains unclear. Studies in our laboratory demonstrated that cells of the immune system produce a novel TSH? splice variant (TSH?v), the first functional splice variant of TSH? to be identified for mice and humans. Importantly, this is the sole form of TSH? produced by the immune system. We demonstrated that TSH?v expression is increased in the thyroid of mice infected with reovirus or L. monocytogenes, due principally to the trafficking of TSH?v-producing cells to the thyroid during infection. Based on those and other studies, we propose that immune system TSH?v plays a key role in regulating host metabolic activity by modulating thyroid hormone synthesis. In this R21 grant, we will test the hypothesis that suppression of TSH?v expression in the cells of the immune system will cause dysregulated thyroid hormone synthesis, altered host metabolic activity, and disrupted bone morphogenesis in mice under normal healthy conditions, and in pathophysiologic settings during infection. There are two Specific Aims for the project. Aim 1 To assess the effects of TSH?v suppression on basal metabolism, thyroid hormone synthesis, and bone morphogenesis in normal mice. Aim 2. To assess the effects of TSH?v knockdown on basal metabolism, thyroid hormone synthesis, and bone morphogenesis during viral and bacterial infection. We will use two approaches to suppress TSH?v. In the first, shRNA-TSH?v lentivirus will be used to suppress TSH?v in bone marrow hematopoietic cells and peripheral leukocytes. In the second, we will knockout TSH?v in animals by Crispr/Cas9 gene editing. These studies will be the first to directly examine the functional involvement of immune system TSH?v during normal homeostatic conditions and during times of immunological stress. They are expected to greatly expand our knowledge of immune-endocrine interactions in ways not appreciated to the present.